During
embryonic development, inductive signals, such as Shh and
BMPs, determine the initial fate of a cell as well the partitioning
of the developing structures into organizing centers, such
as the dorsal or the ventral neural tube. These newly organized
structures, in turn, induce the expression of bHLHL transcription
factors that regulate the patterning into different zones.
This process is particularly pronounced in the generation
of the nervous system, where the patterning genes, by interacting
with the downstream proneural genes, specify the neuronal
subtype identity and the time-schedule regulating how long
a neuron of a certain type will be generated during neurogenesis.
In fact, during the development of the nervous system, precursor
cells divide a limited number of times before they arrest
and terminally differentiate into postmitotic cells.
These latter events are controlled
by a tightly coordinated action between proneural genes and
cell cycle genes. For instance, Mash1 induces p27, an inhibitor
of cyclin-dependent kinases (CDKs), from which ensues the
activation of the key cell cycle inhibitor Retinoblastoma
protein (pRb). Such ability to control cell cycle by modulating
the expression of cell cycle molecules appears to be a feature
common to many other neurogenic molecules (e.g. Prospero,
XBF-1), in several neuronal systems, and is necessary for
a correct attainment of neuronal specification and differentiation.
On
the other hand, cell cycle inhibitory molecules have by themselves
profound effects on neuronal differentiation. For instance,
it is known that ablation of cyclin D2 gene affects the formation
of cerebellum, with the loss of granule cells and stellate
interneurons, whereas, in mice ablated of the Rb gene, neuroblasts
do not undergo cell cycle arrest and then encounter apoptosis.
Thus, there
is strong evidence for close molecular links between cell
cycle control and neuronal differentiation, but the underlying
mechanisms are only poorly understood. It is thus of key importance
to ascertain the mutual interplay of these two processes,
neuronal specification and control of cell cycle. The information
derived from these studies can have a profound influence in
fields such as tumorigenesis and stem cell culture.
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